CLZ10_COCLU
ID CLZ10_COCLU Reviewed; 723 AA.
AC A0A345BJN1;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 07-NOV-2018, sequence version 1.
DT 03-AUG-2022, entry version 14.
DE RecName: Full=Phenylalanine ammonia-lyase {ECO:0000303|PubMed:28605916};
DE Short=PAL {ECO:0000303|PubMed:28605916};
DE EC=4.3.1.24 {ECO:0000255|RuleBase:RU003955};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein clz10 {ECO:0000303|PubMed:28605916};
DE AltName: Full=Zaragozic acid A biosynthesis cluster protein 10 {ECO:0000303|PubMed:28605916};
GN Name=clz10 {ECO:0000303|PubMed:28605916};
OS Cochliobolus lunatus (Filamentous fungus) (Curvularia lunata).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC Pleosporomycetidae; Pleosporales; Pleosporineae; Pleosporaceae; Curvularia.
OX NCBI_TaxID=5503;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, AND
RP PATHWAY.
RC STRAIN=ATCC 74067;
RX PubMed=28605916; DOI=10.1021/acs.orglett.7b01534;
RA Liu N., Hung Y.S., Gao S.S., Hang L., Zou Y., Chooi Y.H., Tang Y.;
RT "Identification and heterologous production of a benzoyl-primed
RT tricarboxylic acid polyketide intermediate from the zaragozic acid A
RT biosynthetic pathway.";
RL Org. Lett. 19:3560-3563(2017).
CC -!- FUNCTION: Phenylalanine ammonia-lyase; part of the gene cluster that
CC mediates the biosynthesis of squalestatin S1 (SQS1, also known as
CC zaragozic acid A), a heavily oxidized fungal polyketide that offers
CC potent cholesterol lowering activity by targeting squalene synthase
CC (SS) (PubMed:28605916). SQS1 is composed of a 2,8-
CC dioxobicyclic[3.2.1]octane-3,4,5-tricarboxyclic acid core that is
CC connected to two lipophilic polyketide arms (PubMed:28605916). These
CC initial steps feature the priming of an unusual benzoic acid starter
CC unit onto the highly reducing polyketide synthase clz14, followed by
CC oxaloacetate extension and product release to generate a tricarboxylic
CC acid containing product (PubMed:28605916). The phenylalanine ammonia
CC lyase (PAL) clz10 and the acyl-CoA ligase clz12 are involved in
CC transforming phenylalanine into benzoyl-CoA (PubMed:28605916). The
CC citrate synthase-like protein clz17 is involved in connecting the C-
CC alpha-carbons of the hexaketide chain and oxaloacetate to afford the
CC tricarboxylic acid unit (PubMed:28605916). The potential hydrolytic
CC enzymes, clz11 and clz13, are in close proximity to pks2 and may
CC participate in product release (PubMed:28605916). On the other side,
CC the tetraketide arm is synthesized by a the squalestatin tetraketide
CC synthase clz2 and enzymatically esterified to the core in the last
CC biosynthetic step, by the acetyltransferase clz6 (By similarity). The
CC biosynthesis of the tetraketide must involve 3 rounds of chain
CC extension (By similarity). After the first and second rounds methyl-
CC transfer occurs, and in all rounds of extension the ketoreductase and
CC dehydratase are active (By similarity). The enoyl reductase and C-MeT
CC of clz2 are not active in the final round of extension (By similarity).
CC The acetyltransferase clz6 appears to have a broad substrate
CC selectivity for its acyl CoA substrate, allowing the in vitro synthesis
CC of novel squalestatins (By similarity). The biosynthesis of SQS1
CC requires several oxidative steps likely performed by oxidoreductases
CC clz3, clz15 and clz16 (Probable). Finally, in support of the
CC identification of the cluster as being responsible for SQS1 production,
CC the cluster contains a gene encoding a putative squalene synthase (SS)
CC clz20, suggesting a likely mechanism for self-resistance (Probable).
CC {ECO:0000250|UniProtKB:A0A3G1DJK5, ECO:0000269|PubMed:28605916,
CC ECO:0000305|PubMed:28605916}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-phenylalanine = (E)-cinnamate + NH4(+);
CC Xref=Rhea:RHEA:21384, ChEBI:CHEBI:15669, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:58095; EC=4.3.1.24;
CC Evidence={ECO:0000255|RuleBase:RU003955};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:28605916}.
CC -!- PATHWAY: Phenylpropanoid metabolism; trans-cinnamate biosynthesis;
CC trans-cinnamate from L-phenylalanine: step 1/1.
CC {ECO:0000255|RuleBase:RU003955}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|RuleBase:RU003955}.
CC -!- PTM: Contains an active site 4-methylidene-imidazol-5-one (MIO), which
CC is formed autocatalytically by cyclization and dehydration of residues
CC Ala-Ser-Gly. {ECO:0000250|UniProtKB:Q68G84}.
CC -!- SIMILARITY: Belongs to the PAL/histidase family. {ECO:0000305}.
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DR EMBL; MF806529; AXF50644.1; -; Genomic_DNA.
DR EMBL; MF806533; AXF50657.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A345BJN1; -.
DR SMR; A0A345BJN1; -.
DR UniPathway; UPA00713; UER00725.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0045548; F:phenylalanine ammonia-lyase activity; IEA:UniProtKB-EC.
DR GO; GO:0009800; P:cinnamic acid biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0006559; P:L-phenylalanine catabolic process; IEA:UniProtKB-KW.
DR CDD; cd00332; PAL-HAL; 1.
DR Gene3D; 1.10.274.20; -; 1.
DR Gene3D; 1.10.275.10; -; 1.
DR InterPro; IPR001106; Aromatic_Lyase.
DR InterPro; IPR024083; Fumarase/histidase_N.
DR InterPro; IPR008948; L-Aspartase-like.
DR InterPro; IPR022313; Phe/His_NH3-lyase_AS.
DR InterPro; IPR005922; Phe_NH3-lyase.
DR InterPro; IPR023144; Phe_NH3-lyase_shielding_dom_sf.
DR PANTHER; PTHR10362; PTHR10362; 1.
DR Pfam; PF00221; Lyase_aromatic; 1.
DR SUPFAM; SSF48557; SSF48557; 1.
DR TIGRFAMs; TIGR01226; phe_am_lyase; 1.
DR PROSITE; PS00488; PAL_HISTIDASE; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Lyase; Phenylalanine catabolism; Phenylpropanoid metabolism.
FT CHAIN 1..723
FT /note="Phenylalanine ammonia-lyase"
FT /id="PRO_0000452633"
FT ACT_SITE 77
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT BINDING 342
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT BINDING 443
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT BINDING 471
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT MOD_RES 183
FT /note="2,3-didehydroalanine (Ser)"
FT /evidence="ECO:0000250|UniProtKB:P11544"
FT CROSSLNK 182..184
FT /note="5-imidazolinone (Ala-Gly)"
FT /evidence="ECO:0000250|UniProtKB:P11544"
SQ SEQUENCE 723 AA; 78028 MW; E0C2F4AF5CFB9DD4 CRC64;
MSSRPLLTLA LSLHDRLDEL SNRGQIHLVG YDLDVAAVAA VARHECLPIV NDGEVIARLS
ESTEILQRSY KGSTTIYGVH TGFGGSADTR PDDSSGLSKG LMQLLQTGVL VVENLDIPGL
DTPQDVIPES MPSSWTRATT VVRINQCIRG HSAIRHQTVK SLLKLVAAQI TPIVPLRGSI
SASGDLMPLS YIAGTLEGSP DIYVTKGGGK SAKIISAHDA LGEIGMEPLR LGPREGLGLV
NGTATSAATA SLAVLDAIQL TLLSTGLTCL VSEGMAARVE WLHPFIAETR PHPGQREVAE
IMRAFLKGSR LVSGLEGEAS THQHTLNVRP DEGLPQDRYP LRTSPQWLGP QFEDILLAHS
QISVELNSTS DNPLTNLKTG AIHHGGNFQA TSITSAVEKI RTSLQMVGKL LFSQCTEMIN
HQMNAGLPPN LAADDPSASF CCKGLDINIA AYQSELSYLS NSISNHVQSA EMHNQAVNSL
AFLSTRYTIK AIELLGMMVA GVLYAACQAM DLRVMHATFL ETVTATLQKA IADLLPNGFE
AEDVERSLAS AIRGLRNAWW NNAGSDASER CSLAAVAFVQ VLCDPSKHHT DTPKVKVCLD
LTAKEMRELQ DDVRSHLSQA YHKHHSAFLE KPTTEEYIGE GSKALYLWAR QDLGIPMNRG
LVDHPSPGSI GKRTIGSYVS MIYQGIQDGR LFQRFATVGR EVGLGNGGTN GIRKRAYAEY
EIS
